Posterior Reversible Encephalopathy Syndrome in Clinical Toxicology: A Systematic Review of Published Case Reports

International audienceBackground: Posterior reversible encephalopathy syndrome (PRES) is a rare clinical and radiological entity characterized by a typical brain edema. Although several case reports have described PRES in a context of poisoning, to our knowledge, a comprehensive assessment has not been performed. The aim of this systematic review was to raise awareness on poisoning-specific PRES features and to encourage consistent and detailed reporting of substance abuse-and drug overdose-associated PRES. Methods: Medline/PubMed, Web of Science, and PsycINFO were screened through May 31, 2019, to systematically identify case reports and case series describing PRES associated with poisoning (i.e., alcohol, drugs, illicit drugs, natural toxins, chemical substances) in accidental context, intentional overdose, and substance abuse. The methodological quality of eligible case reports/series was assessed. Patients and exposure characteristics were recorded; relevant toxicological, radiological, and clinical data were extracted. Results: Forty-one case reports and one case series reporting 42 unique cases were included. The median time to PRES onset from the start of exposure was 3 days (IQR 2-10). Acute high blood pressure, visual disturbance, and seizure were reported in 70, 55, and 50% of patients, respectively. The initial clinical presentation was alertness disorders in 64% of patients. Nine patients (21%) required mechanical ventilation. One-third of patients had at least one risk factor for PRES such as chronic hypertension (17%) or acute/chronic kidney failure (24%). The main imaging pattern (67%) was the combination of classical parieto-occipital edema with another anatomical region (e.g., frontal, basal ganglia, posterior fossa involvement). Vasogenic edema was found in 86% of patients. Intracranial hemorrhage occurred in 14% of patients. Both brain infarction and reversible cerebral vasoconstriction syndrome were diagnosed in 5% of patients. Three patients (12%, 3/25) had non-reversible lesions on follow-up magnetic resonance imaging. The median time required to hospital discharge was 14 days (IQR 7-18). Mortality and neurological recurrence rate were null. Conclusions: Comorbidities such as chronic hypertension and kidney failure were less frequent than in patients with other PRES etiologies. Imaging analysis did not highlight a specific pattern for poisoning-induced PRES. Although less described, PRES in the context of poisoning, which shares most of the clinical and radiological characteristics of other etiologies, is not to be ignored

Lack of impact of iodinated contrast media on kidney cell-cycle arrest biomarkers in critically ill patients

Abstract Background Iodinated contrast media may contribute to acute kidney injury. However, several recent works suggest that this toxicity is minimal in the clinical setting. Recently, urinary G1 cell-cycle arrest proteins tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin like growth factor binding protein 7 (IGFBP-7) were identified as highly sensitive and specific biomarkers for early detection of kidney aggression. The impact of contrast administration on those biomarkers has not been specifically evaluated but could provide clues about the toxicity of contrast media. This study aimed at measuring changes in TIMP-2 and IGFBP-7 urinary concentrations before and after a contrast-enhanced computed tomography in critically ill patients. Methods 77 patients were included in a prospective observational cohort study. Urinary [TIMP -2]·[IGFBP-7] was measured before, 6 and 24 h after contrast infusion. Urine output and serum creatinine were followed 3 days. Results Median [TIMP-2]·[IGFBP-7] was 0.06 [interquartile range 0.04;0.26], 0.07 [0.03;0.34] and 0.10 [0.04;0.37] (ng/mL)2/1000 respectively before, 6 and 24 h after contrast infusion. Individual changes from baseline were − 0.01 [− 0.11;0.11] and 0.00 [− 0.10;0.09] (ng/ml)2/1000 at 6 and 24 h. These changes were not higher among the patients increasing their Kidney Disease Improving Global Outcome (KDIGO) classification within 3 days after contrast infusion (n = 14 [18%] based on creatinine criterion only, n = 42 [55%] based on creatinine and urine output). Conclusions Changes in [TIMP-2]·[IGFBP-7] urinary concentration after contrast-enhanced computed tomography were insignificant, suggesting minimal kidney aggression by modern iodinated contrast media

Arginine Vasopressin and Posterior Reversible Encephalopathy Syndrome Pathophysiology: the Missing Link?

International audiencePosterior reversible encephalopathy syndrome (PRES) is a clinicoradiological entity characterized by a typical brain edema. Its pathogenesis is still debated through hypoperfusion and hyperperfusion theories, which have many limitations. As PRES occurs almost exclusively in clinical situations with arginine vasopressin (AVP) hypersecretion, such as eclampsia and sepsis, we hypothesize that AVP plays a central pathophysiologic role. In this review, we discuss the genesis of PRES and its symptoms through this novel approach. We theorize that AVP axis stimulation precipitates PRES development through an increase in AVP secretion or AVP receptor density. Activation of vasopressin V1a receptors leads to cerebral vasoconstriction, causing endothelial dysfunction and cerebral ischemia. This promotes cytotoxic edema through hydromineral transglial flux dysfunction and may increase endothelial permeability, leading to subsequent vasogenic brain edema. If our hypothesis is confirmed, it opens new perspectives for better patient monitoring and therapies targeting the AVP axis in PRES

Healthcare trajectories before and after critical illness: population-based insight on diverse patients clusters

International audienceBackground: The post intensive care syndrome (PICS) gathers various disabilities, associated with a substantial healthcare use. However, patients' comorbidities and active medical conditions prior to intensive care unit (ICU) admission may partly drive healthcare use after ICU discharge. To better understand retative contribution of critical illness and PICS-compared to pre-existing comorbidities-as potential determinant of post-critical illness healthcare use, we conducted a population-based evaluation of patients' healthcare use trajectories.Results: Using discharge databases in a 2.5-million-people region in France, we retrieved, over 3 years, all adult patients admitted in ICU for septic shock or acute respiratory distress syndrome (ARDS), intubated at least 5 days and discharged alive from hospital: 882 patients were included. Median duration of mechanical ventilation was 11 days (interquartile ranges [IQR] 8;20), mean SAPS2 was 49, and median hospital length of stay was 42 days (IQR 29;64). Healthcare use (days spent in healthcare facilities) was analyzed 2 years before and 2 years after ICU admission. Prior to ICU admission, we observed, at the scale of the whole study population, a progressive increase in healthcare use. Healthcare trajectories were then explored at individual level, and patients were assembled according to their individual pre-ICU healthcare use trajectory by clusterization with the K-Means method. Interestingly, this revealed diverse trajectories, identifying patients with elevated and increasing healthcare use (n = 126), and two main groups with low (n = 476) or no (n = 251) pre-ICU healthcare use. In ICU, however, SAPS2, duration of mechanical ventilation and length of stay were not different across the groups. Analysis of post-ICU healthcare trajectories for each group revealed that patients with low or no pre-ICU healthcare (which represented 83% of the population) switched to a persistent and elevated healthcare use during the 2 years post-ICU.Conclusion: For 83% of ARDS/septic shock survivors, critical illness appears to have a pivotal role in healthcare trajectories, with a switch from a low and stable healthcare use prior to ICU to a sustained higher healthcare recourse 2 years after ICU discharge. This underpins the hypothesis of long-term critical illness and PICS-related quantifiable consequences in healthcare use, measurable at a population level

Experimental Models of Posterior Reversible Encephalopathy Syndrome: A Review From Pathophysiology to Therapeutic Targets.

International audiencePosterior reversible encephalopathy syndrome (PRES) is a clinical and radiological entity characterized by nonspecific symptomatology (eg, headache, visual disturbances, encephalopathy, and seizures) and classically cortical and subcortical vasogenic edema predominantly affecting the parietooccipital region. PRES etiologies are usually dichotomized into toxic PRES (eg, antineoplastic drugs, illicit drugs) and clinical condition-associated PRES (eg, acute hypertension, dysimmune disorders). Although the pathophysiology of PRES remains elusive, 2 main pathogenic hypotheses have been suggested: cerebral hyperperfusion due to acute hypertension and cerebral hypoperfusion related to endothelial dysfunction. Research into the pathogenesis of PRES has emerged through the development of animal models in the last decade. The motivation for developing a suitable PRES model is 2-fold: to fill in knowledge gaps of the pathophysiological mechanisms involved, and to open new perspectives for clinical assessment of pharmacological targets to improve therapeutic management of PRES. All current models of PRES have a hypertensive background, on which other triggers (acute hypertension, inflammatory, drug toxicity) have been added to address specific facets of PRES (eg, seizures). The initial model consisted in inducing a reduced uterine perfusion pressure that mimics preeclampsia, a leading cause of PRES. More recently, a model of stroke-prone spontaneously hypertensive rats on high-salt diet, originally developed for hypertensive small vessel disease and vascular cognitive impairment, has been studied in PRES. This review aims to discuss, depending on the research objective, the benefits and limitations of current experimental approaches and thus to define the desirable characteristics for studying the pathophysiology of PRES and developing new therapies

A Machine Learning Approach to Estimate the Glomerular Filtration Rate in Intensive Care Unit Patients Based on Plasma Iohexol Concentrations and Covariates

International audienceObjective This work aims to evaluate whether a machine learning approach is appropriate to estimate the glomerular filtrationrate in intensive care unit patients based on sparse iohexol pharmacokinetic data and a limited number of predictors.Methods Eighty-six unstable patients received 3250 mg of iohexol intravenously and had nine blood samples collected 5,30, 60, 180, 360, 540, 720, 1080, and 1440 min thereafter. Data splitting was performed to obtain a training (75%) and a testset (25%). To estimate the glomerular filtration rate, 37 candidate potential predictors were considered and the best machinelearning approach among multivariate-adaptive regression spline and extreme gradient boosting (Xgboost) was selected basedon the root-mean-square error. The approach associated with the best results in a ten-fold cross-validation experiment wasthen used to select the best limited combination of predictors in the training set, which was finally evaluated in the test set.Results The Xgboost approach yielded the best performance in the training set. The best combination of covariates comprisediohexol concentrations at times 180 and 720 min; the relative deviation from these theoretical times; the difference betweenthese two concentrations; the Simplified Acute Physiology Score II; serum creatinine; and the fluid balance. It resulted in aroot-mean-square error of 6.2 mL/min and an r2 of 0.866 in the test set. Interestingly, the eight patients in the test set with aglomerular filtration rate < 30 mL/min were all predicted accordingly.Conclusions Xgboost provided accurate glomerular filtration rate estimation in intensive care unit patients based on twotimed blood concentrations after iohexol intravenous administration and three additional predictors

Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells

International audienceHigh concentrations of extracellular ATP (eATP) resulting from cell damage may be found during an ischemia/reperfusion (I/R) episode at the site of injury. eATP activates purinergic receptors in dendritic cells (DCs) and may inhibit inflammation. This immunosuppressive activity could be of interest in the field of I/R, which is an inflammatory condition involved in myocardial infarction, stroke, and solid organ transplantation. However, the specific purinergic receptor responsible for this effect remains to be identified. In this study, we report that eATP induced maturation of human monocyte-derived DCs. Additionally, eATP inhibited IL-12 production whereas IL-10 levels remained unchanged in activated DCs. These effects were prevented by the P2Y11R antagonist NF340. Interestingly, a 5-h hypoxia prevented the effects of eATP on cytokine production whereas a 1-h hypoxia did not affect the eATP-mediated decrease of IL-12 and IL-6. We showed a time-dependent downregulation of P2Y11R at both mRNA and protein levels that was prevented by knocking down hypoxia-inducible factor-1α. In this study, we showed an immunosuppressive role of P2Y11R in human DCs. Additionally, we demonstrated that the time-dependent downregulation of P2Y11R by hypoxia orientates DCs toward a proinflammatory phenotype that may be involved in post-I/R injuries as observed after organ transplantation

Nasal high-flow bronchodilator nebulization: a randomized cross-over study

Abstract Background There is an absence of controlled clinical data showing bronchodilation effectiveness after nebulization via nasal high-flow therapy circuits. Results Twenty-five patients with reversible airflow obstruction received, in a randomized order: (1) 2.5 mg albuterol delivered via a jet nebulizer with a facial mask; (2) 2.5 mg albuterol delivered via a vibrating mesh nebulizer placed downstream of a nasal high-flow humidification chamber (30 L/min and 37 °C); and (3) nasal high-flow therapy without nebulization. All three conditions induced significant individual increases in forced expiratory volume in one second (FEV1) compared to baseline. The median change was similar after facial mask nebulization [+ 350 mL (+ 180; + 550); + 18% (+ 8; + 30)] and nasal high flow with nebulization [+ 330 mL (+ 140; + 390); + 16% (+ 5; + 24)], p = 0.11. However, it was significantly lower after nasal high-flow therapy without nebulization [+ 50 mL (− 10; + 220); + 3% (− 1; + 8)], p = 0.0009. FEV1 increases after facial mask and nasal high-flow nebulization as well as residual volume decreases were well correlated (p < 0.0001 and p = 0.01). Both techniques showed good agreement in terms of airflow obstruction reversibility (kappa 0.60). Conclusion Albuterol vibrating mesh nebulization within a nasal high-flow circuit induces similar bronchodilation to standard facial mask jet nebulization. Beyond pharmacological bronchodilation, nasal high flow by itself may induce small but significant bronchodilation

A Hybrid Model Associating Population Pharmacokinetics with Machine Learning: A Case Study with Iohexol Clearance Estimation

International audienceBackground Maximum a posteriori Bayesian estimation (MAP-BE) based on a limited sampling strategy and a population pharmacokinetic model is frequently used to estimate pharmacokinetic parameters in individuals, however with some uncertainty (bias). Recent works have shown that the performance in individual estimation or pharmacokinetic parameters can be improved by combining population pharmacokinetic and machine learning algorithms. Objective: The objective of this work was to investigate the use of a hybrid machine learning/population pharmacokinetic approach to improve individual iohexol clearance estimation. Methods The reference iohexol clearance values were derived from 500 simulated profiles (samples collected between 0.1 and 24.7 h) using a population pharmacokinetic model we recently developed in Monolix and obtained using all the concentration timepoints available. Xgboost and glmnet algorithms able to predict the error of MAP-BE clearance estimates based on a limited sampling strategy (0.1 h, 1 h, and 9 h) versus reference values were developed in a training subset (75%) and were evaluated in a testing subset (25%) and in 36 real patients. Results The MAP-BE limited sampling strategy estimated clearance was corrected by the machine learning predicted error leading to a decrease in root mean squared error by 29% and 24%, and in the percentage of profiles with the mean prediction error out of the ± 20% bias by 60% and 40% in the external validation dataset for the glmnet and Xgboost machine learning algorithms, respectively. These results were attributable to a decrease in the eta-shrinkage (shrinkage for a MAP-BE limited sampling strategy = 32.4%, glmnet = 18.2%, and Xgboost = 19.4% in the external dataset). Conclusions In conclusion, this hybrid algorithm represents a significant improvement in comparison to MAP-BE estimation alone